Although the interactions between invading pathogens and the host's resident microbiota are clearly important to the outcome of many infections, they remain poorly understood with few experimental systems in which they can be explored at a molecular mechanistic level. We have recently identified striking differences between closely related pathogens of the genus Bordetella in their interactions with host microbiome that can explain important aspects of their biology, including host specificity and pathology. B. bronchiseptica efficiently colonizes the upper respiratory tracts (URT) of mice (ID50<10cfu) and displaces the resident microflora in the process. B. pertussis, which causes highly contagious Whooping Cough in humans, poorly colonizes mice (ID50>1000cfu) and does not affect resident microbiota. Testing the hypothesis that resident microbiota of mice inhibit colonization, we observed that clearing the URT of bacteria allows B. pertussis to efficiently colonize (ID50<100). We have now extended this work by identifying specific microorganisms that can prevent B. pertussis colonization. This application will 1. Define the ability of resident microorganism(s) to inhibit B. pertussis colonization of mice, 2. Identify ecological mechanisms of competition amongst nasal microbiota and invading bordetellae, and 3. Determine the molecular mechanisms by which B. bronchiseptica clears microflora from the URT. This exceptionally powerful and tractable experimental system will allow us to study the complex interactions between invading pathogen and host resident microbiota to satisfying molecular mechanisms. Improved understanding of these interactions is likely to inform views of the many other mucosal pathogens for which there is not such a powerful host infection experimental system.